Diabetes is one of the most serious and urgent health concerns in the U.S. and worldwide. Because insulin resistance in peripheral organs, such as skeletal muscle, precedes the onset of type 2 diabetes, it is crucial to better understand the mechanisms of peripheral insulin resistance for the treatment of type 2 diabetes. Brown adipose tissue (BAT), which dissipates energy in the form of heat, significantly contributes to an improvement in systemic and peripheral glucose homeostasis under obesity conditions. While the conventional consensus has been that such improvement is a metabolic consequence of BAT's anti-obesity effects, new evidence indicates that BAT may directly control glucose homeostasis by secreting adipokines that act directly on peripheral tissues. Our long-term goal is to understand the mechanisms by which BAT and metabolic organs, such as skeletal muscle, communicate with each other to regulate whole-body energy metabolism through secreted molecules. We recently identified a previously unappreciated secreted molecule from BAT, BolA Family Member 3 (Bola3). Our preliminary data indicate that Bola3 acts on skeletal muscle to enhance glucose uptake and the enzymatic activity of pyruvate dehydrogenase (PDH), a key metabolic regulator of glucose oxidation. Hence, our current objective is to test the hypothesis that Bola3 is a BAT-derived adipokine that regulates glucose homeostasis and insulin sensitivity by PDH activation in skeletal muscle. To test this hypothesis, we will pursue the following specific aims: In aim 1, we will test the genetic requirement of BAT-derived Bola3 for maintaining energy and glucose homeostasis in vivo. We will also assess the therapeutic potential of Bola3 by examining the extent to which Bola3 improves peripheral insulin sensitivity in vivo. In aim 2, we will conduct a series of biochemical analyses to investigate the molecular mechanisms by which Bola3 controls glucose metabolism and PDH activity in skeletal muscle. The expected outcome of these studies is to characterize a completely novel BAT-derived secretory factor that regulates systemic and peripheral glucose homeostasis. Our findings will have a significant impact, because this study will provide a new entity that can improve systemic glucose homeostasis and reverse insulin resistance in skeletal muscle. Our study will also develop the innovative concept that BAT is not simply a heat-generating organ, but can also function as an endocrine organ to control glucose homeostasis and peripheral insulin sensitivity.